Cholecystokinin Receptor-Targeted Polyplex Nanoparticle Inhibits Growth and Metastasis of Pancreatic Cancer

Abstract

Background & AimsPancreatic ductal adenocarcinoma (PDAC) remains the most aggressive malignancy with the lowest 5-year survival rate of all cancers in part owing to the lack of tumor-specific therapy and the rapid metastatic nature of this cancer. The gastrointestinal peptide gastrin is a trophic peptide that stimulates growth of PDAC in an autocrine fashion by interaction with the cholecystokinin receptor that is overexpressed in this malignancy.MethodsWe developed a therapeutic novel polyplex nanoparticle (NP) that selectively targets the cholecystokinin receptor on PDAC. The NP was characterized in vitro and stability testing was performed in human blood. The effects of the target-specific NP loaded with gastrin small interfering RNA (siRNA) was compared with an untargeted NP and with an NP loaded with a scrambled siRNA in vitro and in 2 orthotopic models of PDAC. A polymerase chain reaction metastasis array examined differentially expressed genes from control tumors compared with tumors of mice treated with the targeted polyplex NP.ResultsThe polyplex NP forms a micelle that safely delivers specific gastrin siRNA to the tumor without off-target toxicity. Consistent with these findings, cellular uptake was confirmed only with the targeted fluorescently labeled NP by confocal microscopy in vitro and by IVIS fluorescent based imaging in mice bearing orthotopic pancreatic cancers but not found with untargeted NPs. Tumor uptake and release of the gastrin siRNA NP was verified by decreased cellular gastrin gene expression by quantitative reverse-transcription polymerase chain reaction and peptide expression by immunohistochemistry. Growth of PDAC was inhibited in a dose-related fashion in cell culture and in vivo. The targeted NP therapy completely blocked tumor metastasis and altered tumor-specific genes.ConclusionsOur polyplex nanoparticle platform establishes both a strong foundation for the development of receptor-targeted therapeutics and a unique approach for the delivery of siRNA in vivo, thus warranting further exploration of this approach in other types of cancers.

Vaccine against gastrin, a polyclonal antibody stimulator, decreases pancreatic cancer metastases

“…Watson and colleagues (60) previously showed that passive immunization with rabbit PAS-induced antibodies decreased the number and size of metastases of colorectal cancer in an immune deficient mouse. We formerly demonstrated that a nanoparticle delivering siRNA to gastrin also completely prevented metastases in athymic nude mice bearing human pancreatic tumors (8). Thus strategies that decrease circulating or endogenous tumor production of gastrin have been shown to inhibit metastases from gastrointestinal cancers.…”

Nonviral siRNA delivery systems for pancreatic cancer therapy

“…Therefore, different gastrin‐mediated delivery systems have been designed to target gastrin mRNA in pancreatic cancer cells. In one of these studies, gastrin‐10‐polyethylene glycol‐poly( l ‐lysine) (Ga‐10‐[PEG]5k‐PLL27) has been developed by Burks et al (2018) to deliver gastrin siRNA into the pancreatic tumor cells. The Ga‐conjugated carrier revealed greater gene silencing of gastrin in PANC‐1 cells than unmodified ones.…”

Non-viral siRNA delivery systems for pancreatic cancer therapy

“…Therefore, to target gastrin mRNA in pancreatic cancer cells, some researchers use gastrin-mediated delivery. In one of these studies, gastrinpolyethylene glycol-poly(L-lysine) (Ga-[PEG]5k-PLL27) has been designed by Burks and his co-workers (Burks et al, 2018) to deliver gastrin siRNA into the pancreatic tumor cells. The Ga-conjugated carrier revealed greater gene silencing of gastrin in PANC-1 cells than unmodified ones.…”